Centre for Youth Mental Health - Research Publications

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    New generation antidepressants for depression in children and adolescents: a network meta-analysis (Review)
    Hetrick, SE ; McKenzie, JE ; Bailey, AP ; Sharma, V ; Moller, CI ; Badcock, PB ; Cox, GR ; Merry, SN ; Meader, N (Wiley, 2021-05-24)
    BACKGROUND: Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications. OBJECTIVES: To investigate, via network meta-analysis (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD) in terms of depression, functioning, suicide-related outcomes and other adverse outcomes. The impact of age, treatment duration, baseline severity, and pharmaceutical industry funding was investigated on clinician-rated depression (CDRS-R) and suicide-related outcomes. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR)), together with Ovid Embase, MEDLINE and PsycINFO till March 2020. SELECTION CRITERIA: Randomised trials of six to 18 year olds of either sex and any ethnicity with clinically diagnosed major depressive disorder were included. Trials that compared the effectiveness of newer generation antidepressants with each other or with a placebo were included. Newer generation antidepressants included: selective serotonin reuptake inhibitors; selective norepinephrine reuptake inhibitors (SNRIs); norepinephrine reuptake inhibitors; norepinephrine dopamine reuptake inhibitors; norepinephrine dopamine disinhibitors (NDDIs); and tetracyclic antidepressants (TeCAs). DATA COLLECTION AND ANALYSIS: Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed risk of bias. We analysed dichotomous data as Odds Ratios (ORs), and continuous data as Mean Difference (MD) for the following outcomes: depression symptom severity (clinician rated), response or remission of depression symptoms, depression symptom severity (self-rated), functioning, suicide related outcomes and overall adverse outcomes. Random-effects network meta-analyses were conducted in a frequentist framework using multivariate meta-analysis. Certainty of evidence was assessed using Confidence in Network Meta-analysis (CINeMA). We used "informative statements" to standardise the interpretation and description of the results. MAIN RESULTS: Twenty-six studies were included. There were no data for the two primary outcomes (depressive disorder established via clinical diagnostic interview and suicide), therefore, the results comprise only secondary outcomes. Most antidepressants may be associated with a "small and unimportant" reduction in depression symptoms on the CDRS-R scale (range 17 to 113) compared with placebo (high certainty evidence: paroxetine: MD -1.43, 95% CI -3.90, 1.04; vilazodone: MD -0.84, 95% CI -3.03, 1.35; desvenlafaxine MD -0.07, 95% CI -3.51, 3.36; moderate certainty evidence: sertraline: MD -3.51, 95% CI -6.99, -0.04; fluoxetine: MD -2.84, 95% CI -4.12, -1.56; escitalopram: MD -2.62, 95% CI -5.29, 0.04; low certainty evidence: duloxetine: MD -2.70, 95% CI -5.03, -0.37; vortioxetine: MD 0.60, 95% CI -2.52, 3.72; very low certainty evidence for comparisons between other antidepressants and placebo). There were "small and unimportant" differences between most antidepressants in reduction of depression symptoms (high- or moderate-certainty evidence). Results were similar across other outcomes of benefit. In most studies risk of self-harm or suicide was an exclusion criterion for the study. Proportions of suicide-related outcomes were low for most included studies and 95% confidence intervals were wide for all comparisons. The evidence is very uncertain about the effects of mirtazapine (OR 0.50, 95% CI 0.03, 8.04), duloxetine (OR 1.15, 95% CI 0.72, 1.82), vilazodone (OR 1.01, 95% CI 0.68, 1.48), desvenlafaxine (OR 0.94, 95% CI 0.59, 1.52), citalopram (OR 1.72, 95% CI 0.76, 3.87) or vortioxetine (OR 1.58, 95% CI 0.29, 8.60) on suicide-related outcomes compared with placebo. There is low certainty evidence that escitalopram may "at least slightly" reduce odds of suicide-related outcomes compared with placebo (OR 0.89, 95% CI 0.43, 1.84). There is low certainty evidence that fluoxetine (OR 1.27, 95% CI 0.87, 1.86), paroxetine (OR 1.81, 95% CI 0.85, 3.86), sertraline (OR 3.03, 95% CI 0.60, 15.22), and venlafaxine (OR 13.84, 95% CI 1.79, 106.90) may "at least slightly" increase odds of suicide-related outcomes compared with placebo. There is moderate certainty evidence that venlafaxine probably results in an "at least slightly" increased odds of suicide-related outcomes compared with desvenlafaxine (OR 0.07, 95% CI 0.01, 0.56) and escitalopram (OR 0.06, 95% CI 0.01, 0.56). There was very low certainty evidence regarding other comparisons between antidepressants. AUTHORS' CONCLUSIONS: Overall, methodological shortcomings of the randomised trials make it difficult to interpret the findings with regard to the efficacy and safety of newer antidepressant medications. Findings suggest that most newer antidepressants may reduce depression symptoms in a small and unimportant way compared with placebo. Furthermore, there are likely to be small and unimportant differences in the reduction of depression symptoms between the majority of antidepressants. However, our findings reflect the average effects of the antidepressants, and given depression is a heterogeneous condition, some individuals may experience a greater response. Guideline developers and others making recommendations might therefore consider whether a recommendation for the use of newer generation antidepressants is warranted for some individuals in some circumstances. Our findings suggest sertraline, escitalopram, duloxetine, as well as fluoxetine (which is currently the only treatment recommended for first-line prescribing) could be considered as a first option. Children and adolescents considered at risk of suicide were frequently excluded from trials, so that we cannot be confident about the effects of these medications for these individuals. If an antidepressant is being considered for an individual, this should be done in consultation with the child/adolescent and their family/caregivers and it remains critical to ensure close monitoring of treatment effects and suicide-related outcomes (combined suicidal ideation and suicide attempt) in those treated with newer generation antidepressants, given findings that some of these medications may be associated with greater odds of these events. Consideration of psychotherapy, particularly cognitive behavioural therapy, as per guideline recommendations, remains important.
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    New generation antidepressants for depression in children and adolescents: a network meta-analysis (Protocol)
    Hetrick, SE ; Meader, N ; Bailey, AP ; Badcock, PB ; Moller, CI ; Cox, GR ; Merry, SN ; McKenzie, JE (Wiley, 2020-07-09)
    Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To investigate, via network meta-analyses (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD). Specific objectives, in order of priority, are to:. estimate the relative effects of newer generation antidepressants compared with placebo and with each other on depression, functioning, suicide-related outcomes and other adverse outcomes; estimate the relative ranking of the included newer generation antidepressants for the outcomes of depression, functioning, suicide-related outcomes and other adverse outcomes; and, examine whether the relative effects on clinician-rated depression symptoms and suicide-related outcomes estimated in objectives 1 and 2 are modified by age, treatment duration, baseline severity and pharmaceutical industry funding of the antidepressant under evaluation.
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    Developing Social Media-Based Suicide Prevention Messages in Partnership With Young People: Exploratory Study
    Robinson, J ; Bailey, E ; Hetrick, S ; Paix, S ; O'Donnell, M ; Cox, G ; Ftanou, M ; Skehan, J (JMIR PUBLICATIONS, INC, 2017-10-04)
    BACKGROUND: Social media is increasingly being used by young people for health-related issues, including communicating about suicide. Due to the concerns about causing distress or inducing suicidal thoughts or behaviors, to date young people neither have been engaged in the development of social media-based suicide prevention interventions nor have interventions focused on educating young people about safe ways to communicate about suicide online. Given the potential that social media holds to deliver messages to vast numbers of people across space and time and the fact that young people often prefer to seek help from their friends and peers, safely educating and engaging young people to develop suicide prevention messages that can be delivered via social media is an obvious next step. OBJECTIVES: The objectives of this study were to (1) provide education to a small number of secondary school students about safe ways to communicate about suicide via social media; (2) engage the same young people in the development of a suite of social media-based suicide prevention multimedia messages; (3) assess the impact of this on participants; and (4) assess the acceptability and safety of the messages developed. METHODS: This study involved two phases. In phase 1, 20 participants recruited from two schools took part in an 8- to 10-week program during which they were provided with psychoeducation about mental health and suicide, including how to talk safely about suicide online, and they were then supported to design and develop their own media messages. These participants completed an evaluation questionnaire at the conclusion of the program. In phase 2, a larger group of participants (n=69), recruited via an opt-in process, viewed the media messages and completed a short questionnaire about each one. RESULTS: Participants in phase 1 enjoyed the program and reported that they learned new skills, such as how to talk safely about suicide online, and felt more able to provide emotional support to others (16/20, 80%). No participants reported that the program made them feel suicidal. Participants in phase 2 generally rated the media messages as safe and acceptable, although some messages were rated more highly than others. CONCLUSIONS: This study suggests that young people can be safely engaged in developing suicide prevention messages, which can be disseminated via social media. Engaging young people in this process may improve the traction that such campaigns will have with other young people. The study also suggests that educating young people regarding how to talk safely about suicide online has multiple benefits and is not associated with distress. Overall, these findings pave the way for new approaches to prevent suicide among young people.
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    Internet-based cognitive behavioural therapy for young people with suicide-related behaviour (Reframe-IT): a randomised controlled trial
    Hetrick, SE ; Yuen, HP ; Bailey, E ; Cox, GR ; Templer, K ; Rice, SM ; Bendall, S ; Robinson, J (BMJ PUBLISHING GROUP, 2017-08)
    BACKGROUND: Suicide-related behaviours are common in young people and associated with a range of negative outcomes. There are few evidence-based interventions; however, cognitive behavioural therapy (CBT) shows promise. Internet delivery of CBT is popular, with potential to increase reach and accessibility. OBJECTIVE: To test the effectiveness of an internet-based CBT program (Reframe-IT) in reducing suicide-related behaviours, depression, anxiety, hopelessness and improving problem solving and cognitive and behavioural skills in school students with suicide-related behaviours. METHODS: A parallel randomised controlled trial testing the effectiveness of Reframe-IT plus treatment as usual (TAU) compared with TAU alone in reducing suicidal ideation, suicide attempts, depression, hopelessness, symptoms of anxiety, negative problem orientation and cognitive and behavioural skill acquisition was undertaken. We recruited students experiencing suicidal ideation from 18 schools in Melbourne, Australia, between August 2013 and December 2016. The intervention comprised eight modules of CBT delivered online over 10 weeks with assessments conducted at baseline, 10 weeks and 22 weeks. FINDINGS: Only 50 of the planned 169 participants were recruited. There were larger improvements in the Reframe-IT group compared with the TAU group for the primary outcome of suicidal ideation (intervention -61.6, SD 41.6; control -47.1, SD 42.3, from baseline to 22-week follow-up intervention); however, differences were non-significant (p=0.593). There were no increases in distress in the majority of participants (91.1%) after completion of each module. Changes in depression and hopelessness partly mediated the effect of acquisition of CBT skills on suicidal ideation. CONCLUSIONS: The trial was underpowered due to difficulties recruiting participants as a result of the complex recruitment procedures that were used to ensure safety of participants. Although there were no significant differences between groups, young people were safely and generally well engaged in Reframe-IT and experienced decreases in suicidal ideation and other symptoms as well as improvements in CBT skills. The study is the first online intervention trial internationally to include young people demonstrating all levels of suicide risk. CLINICAL IMPLICATIONS: Integration of internet-delivered interventions for young people with suicide-related behaviour may result in reductions in these behaviours. Further research is needed, but researchers should feel more confident about being able to safely undertake research with young people who experience these behaviours. TRIAL REGISTRATION NUMBER: ACTRN12613000864729.
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    Psychosocial interventions for self-harm, suicidal ideation and suicide attempt in children and young people: What? How? Who? and Where?
    Cox, G ; Hetrick, S (BMJ PUBLISHING GROUP, 2017-05)
    We reviewed the evidence for the effectiveness of indicated individual psychosocial interventions for the treatment of self-harm, suicidal ideation and suicide attempts in children and young people, with a particular emphasis on the emerging use of electronic methods to deliver psychological interventions. In total, 16 randomised controlled trials (RCTs) were identified, none of which included children under the age of 12 years. Cognitive-behavioural therapy is the most commonly implemented approach in RCTs until now, although problem-solving therapy, interpersonal psychotherapy, social support and distal support methods by provision of a green card and regular receipt of postcards have also been investigated. Young people have been recruited into RCTs within schools, outpatient clinics, emergency departments and inpatient facilities. Face-to-face delivery of therapy has dominated the intervention trials thus far; however, the use of the internet, social media and mobile devices to deliver interventions to young people and other family members allows for a more novel approach to suicide prevention in youth going forward.
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    Treatment-resistant depression in adolescents: is the addition of cognitive behavioral therapy of benefit?
    Hetrick, SE ; Cox, GR ; Merry, SN (DOVE MEDICAL PRESS LTD, 2011)
    BACKGROUND: Many young people with major depression fail first-line treatments. Treatment-resistant depression has various definitions in the literature but typically assumes nonresponse to medication. In young people, cognitive behavioral therapy (CBT) is the recommended first-line intervention, thus the definition of treatment resistance should be expanded. Therefore, our aim was to synthesize the existing evidence of any interventions for treatment-resistant depression, broadly defined, in children and adolescents and to investigate the effectiveness of CBT in this context. METHODS: We used Cochrane Collaboration methodology, with electronic searches of Medline, PsycINFO, Embase, and the Cochrane Depression Anxiety and Neurosis Group trials registers. Only randomized controlled trials were included, and were assessed for risk of bias. Meta- analysis was undertaken where possible and appropriate. RESULTS: Of 953 articles retrieved, four trials were eligible for inclusion. For one study, only the trial registration document was available, because the study was never completed. All other studies were well conducted with a low risk of bias, although one study had a high dropout rate. Two studies assessed the effect of adding CBT to medication. While an assertive trial of antidepressants does appear to lead to benefit, when compared with placebo, there was no significant advantage, in either study, or in a meta-analysis of data from these trials, that clearly demonstrated an additional benefit of CBT. The third trial showed little advantage of a tricyclic antidepressant over placebo in the context of an inpatient admission. CONCLUSION: Few randomized controlled trials have investigated interventions for treatment-resistant depression in young people, and results from these show modest benefit from antidepressants with no additional benefit over medication from CBT. Overall, there is a lack of evidence about effective interventions to treat young people who have failed to respond to evidence-based interventions for depression. Research in this area is urgently required.
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    Psychological and educational interventions for preventing depression in children and adolescents.
    Merry, SN ; Hetrick, SE ; Cox, GR ; Brudevold-Iversen, T ; Bir, JJ ; McDowell, H ( 2011-01-01)
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    CBT, third wave CBT and IPT based interventions to prevent depression in children and adolescents
    Hetrick, S ; Cox, G ; Witt, K ; Bir, J ; Merry, S (Cochrane Collaboration, 2016)
    BACKGROUND: Depression is common in young people. It has a marked negative impact and is associated with self-harm and suicide. Preventing its onset would be an important advance in public health. This is an update of a Cochrane review that was last updated in 2011. OBJECTIVES: To determine whether evidence-based psychological interventions (including cognitive behavioural therapy (CBT), interpersonal therapy (IPT) and third wave CBT)) are effective in preventing the onset of depressive disorder in children and adolescents. SEARCH METHODS: We searched the specialised register of the Cochrane Common Mental Disorders Group (CCMDCTR to 11 September 2015), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). We searched conference abstracts and reference lists of included trials and reviews, and contacted experts in the field. SELECTION CRITERIA: We included randomised controlled trials of an evidence-based psychological prevention programme compared with any comparison control for young people aged 5 to 19 years, who did not currently meet diagnostic criteria for depression. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion and rated their risk of bias. We adjusted sample sizes to take account of cluster designs and multiple comparisons. We contacted trial authors for additional information where needed. We assessed the quality of evidence for the primary outcomes using GRADE. MAIN RESULTS: We included 83 trials in this review. The majority of trials (67) were carried out in school settings with eight in colleges or universities, four in clinical settings, three in the community and four in mixed settings. Twenty-nine trials were carried out in unselected populations and 53 in targeted populations.For the primary outcome of depression diagnosis at medium-term follow-up (up to 12 months), there were 32 trials with 5965 participants and the risk of having a diagnosis of depression was reduced for participants receiving an intervention compared to those receiving no intervention (risk difference (RD) -0.03, 95% confidence interval (CI) -0.05 to -0.01; P value = 0.01). We rated this evidence as moderate quality according to the GRADE criteria. There were 70 trials (73 trial arms) with 13,829 participants that contributed to the analysis for the primary outcome of depression symptoms (self-rated) at the post-intervention time point, with results showing a small but statistically significant effect (standardised mean difference (SMD) -0.21, 95% CI -0.27 to -0.15; P value < 0.0001). This effect persisted to the short-term assessment point (up to three months) (SMD -0.31, 95% CI -0.45 to -0.17; P value < 0.0001; 16 studies; 1558 participants) and medium-term (4 to 12 months) assessment point (SMD -0.12, 95% CI -0.18 to -0.05; P value = 0.0002; 53 studies; 11,913 participants); however, the effect was no longer evident at the long-term follow-up. We rated this evidence as low to moderate quality according to the GRADE criteria.The evidence from this review is unclear with regard to whether the type of population modified the overall effects; there was statistically significant moderation of the overall effect for depression symptoms (P value = 0.0002), but not for depressive disorder (P value = 0.08). For trials implemented in universal populations there was no effect for depression diagnosis (RD -0.01, 95% CI -0.03 to 0.01) and a small effect for depression symptoms (SMD -0.11, 95% CI -0.17 to -0.05). For trials implemented in targeted populations there was a statistically significantly beneficial effect of intervention (depression diagnosis RD -0.04, 95% CI -0.07 to -0.01; depression symptoms SMD -0.32, 95% CI -0.42 to -0.23). Of note were the lack of attention placebo-controlled trials in targeted populations (none for depression diagnosis and four for depression symptoms). Among trials implemented in universal populations a number used an attention placebo comparison in which the intervention consistently showed no effect. AUTHORS' CONCLUSIONS: Overall the results show small positive benefits of depression prevention, for both the primary outcomes of self-rated depressive symptoms post-intervention and depression diagnosis up to 12 months (but not beyond). Estimates of numbers needed to treat to benefit (NNTB = 11) compare well with other public health interventions. However, the evidence was of moderate to low quality using the GRADE framework and the results were heterogeneous. Prevention programmes delivered to universal populations showed a sobering lack of effect when compared with an attention placebo control. Interventions delivered to targeted populations, particularly those selected on the basis of depression symptoms, had larger effect sizes, but these seldom used an attention placebo comparison and there are practical difficulties inherent in the implementation of targeted programmes. We conclude that there is still not enough evidence to support the implementation of depression prevention programmes.Future research should focus on current gaps in our knowledge. Given the relative lack of evidence for universal interventions compared with attention placebo controls and the poor results from well-conducted effectiveness trials of universal interventions, in our opinion any future such trials should test a depression prevention programme in an indicated targeted population using a credible attention placebo comparison group. Depressive disorder as the primary outcome should be measured over the longer term, as well as clinician-rated depression. Such a trial should consider scalability as well as the potential for the intervention to do harm.
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    Interventions for preventing relapse and recurrence of a depressive disorder in children and adolescents
    Cox, GR ; Fisher, CA ; De Silva, S ; Phelan, M ; Akinwale, OP ; Simmons, MB ; Hetrick, SE (WILEY, 2012)
    BACKGROUND: Depressive disorders often begin during childhood or adolescence. There is a growing body of evidence supporting effective treatments during the acute phase of a depressive disorder. However, little is known about treatments for preventing relapse or recurrence of depression once an individual has achieved remission or recovery from their symptoms. OBJECTIVES: To determine the efficacy of early interventions, including psychological and pharmacological interventions, to prevent relapse or recurrence of depressive disorders in children and adolescents. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 1 June 2011). The CCDANCTR contains reports of relevant randomised controlled trials from The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). In addition we handsearched the references of all included studies and review articles. SELECTION CRITERIA: Randomised controlled trials using a psychological or pharmacological intervention, with the aim of preventing relapse or recurrence from an episode of major depressive disorder (MDD) or dysthymic disorder (DD) in children and adolescents were included. Participants were required to have been diagnosed with MDD or DD according to DSM or ICD criteria, using a standardised and validated assessment tool. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all trials for inclusion in the review, extracted trial and outcome data, and assessed trial quality. Results for dichotomous outcomes are expressed as odds ratio and continuous measures as mean difference or standardised mean difference. We combined results using random-effects meta-analyses, with 95% confidence intervals. We contacted lead authors of included trials and requested additional data where possible. MAIN RESULTS: Nine trials with 882 participants were included in the review. In five trials the outcome assessors were blind to the participants' intervention condition and in the remainder of trials it was unclear. In the majority of trials, participants were either not blind to their intervention condition, or it was unclear whether they were or not. Allocation concealment was also unclear in the majority of trials. Although all trials treated participants in an outpatient setting, the designs implemented in trials was diverse, which limits the generalisability of the results. Three trials indicated participants treated with antidepressant medication had lower relapse-recurrence rates (40.9%) compared to those treated with placebo (66.6%) during a relapse prevention phase (odds ratio (OR) 0.34; 95% confidence interval (CI) 0.18 to 0.64, P = 0.02). One trial that compared a combination of psychological therapy and medication to medication alone favoured a combination approach over medication alone, however this result did not reach statistical significance (OR 0.26; 95% CI 0.06 to 1.15). The majority of trials that involved antidepressant medication reported adverse events including suicide-related behaviours. However, there were not enough data to show which treatment approach results in the most favourable adverse event profile. AUTHORS' CONCLUSIONS: Currently, there is little evidence to conclude which type of treatment approach is most effective in preventing relapse or recurrence of depressive episodes in children and adolescents. Limited trials found that antidepressant medication reduces the chance of relapse-recurrence in the future, however, there is considerable diversity in the design of trials, making it difficult to compare outcomes across studies. Some of the research involving psychological therapies is encouraging, however at present more trials with larger sample sizes need to be conducted in order to explore this treatment approach further.
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    Online and Social Media Suicide Prevention Interventions for Young People: A Focus on Implementation and Moderation
    Rice, S ; Robinson, J ; Bendall, S ; Hetrick, S ; Cox, G ; Bailey, E ; Gleeson, J ; Alvarez-Jimenez, M (CANADIAN ACAD CHILD & ADOLESCENT PSYCHIATRY, 2016)
    OBJECTIVE: Suicide remains a major global public health issue for young people. The reach and accessibility of online and social media-based interventions herald a unique opportunity for suicide prevention. To date, the large body of research into suicide prevention has been undertaken atheoretically. This paper provides a rationale and theoretical framework (based on the interpersonal theory of suicide), and draws on our experiences of developing and testing online and social media-based interventions. METHOD: The implementation of three distinct online and social media-based intervention studies, undertaken with young people at risk of suicide, are discussed. We highlight the ways that these interventions can serve to bolster social connectedness in young people, and outline key aspects of intervention implementation and moderation. RESULTS: Insights regarding the implementation of these studies include careful protocol development mindful of risk and ethical issues, establishment of suitably qualified teams to oversee development and delivery of the intervention, and utilisation of key aspects of human support (i.e., moderation) to encourage longer-term intervention engagement. CONCLUSIONS: Online and social media-based interventions provide an opportunity to enhance feelings of connectedness in young people, a key component of the interpersonal theory of suicide. Our experience has shown that such interventions can be feasibly and safely conducted with young people at risk of suicide. Further studies, with controlled designs, are required to demonstrate intervention efficacy.